The present invention relates to deactivation of microorganisms, and more particularly to parametric control in the deactivation of microorganisms using pulsed light. More particularly, the present invention relates to parametric control in the deactivation of microorganisms on packages or their contents using high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum. Even more particularly, the present invention relates to monitoring and controlling key pulsed light parameters in the deactivation of microorganisms on packages or their contents using high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum to verify sterilization has been achieved.
Polyvinyl Chloride (PVC) is a standard, widely used plastic packaging material used to manufacture flexible containers (bags and pouches) for the administration of small volume parenterals (SVPs), often referred to as mini-bags; large volume parenterals (LVPs); and various enteral nutritional and liquid preparations. These containers are often utilized for patient hydration and/or to supply pharmaceutical preparations, medicines, vitamins, nutritionals, and the like. Heretofore, PVC has proven to be advantageous because of its resistance to heat, which allows the containers to be terminally sterilized using high temperature treatment, i.e., sterilized after filling to deactivate microorganisms inside the containers, including microorganisms suspended in liquid content of the container, using high temperature treatment (e.g., autoclaving).
In many cases, an overwrap is also used to help the flexible containers to survive autoclaving (i.e., high temperature treatment), and also to increase the shelf life of parenteral fluids contained therein by providing improved moisture vapor barrier (MVB) properties, as compared to the MVB properties of PVC alone. In many cases, and particularly for SVP packages (or bags), multiple SVP packages are placed into one overwrap package. Disadvantageously, once the one overwrap package has been opened, the shelf life of the individual SVP packages contained therein is limited to approximately 30 days, because of the poor MVB properties of PVC. Thus, if a practitioner opens an overwrap containing SVPs, but does not use all of the SVPs in a timely manner, the SVP packages must be discarded approximately 30 days after the overwrap is opened. The overwrap also represents a significant added packaging cost and contributes to environmental waste.
Using materials other than PVC, such as Olefins (e.g., Polyethylene or Polypropylene); nylon, or a composite material, either laminated or co-extruded structure (including both monolayer and multilayer structures), and the like, for SVP and/or LVP packages offers a number of significant advantages. One advantage is to reduce or eliminate the use of PVC because of environmental concerns. Another advantage of materials such as polyethylene is that they have much better MVB properties than PVC. For example, in some instances, it may be possible to achieve a longer shelf life (for example, 24 months versus the 15 to 18 months achievable with PVC and overwrap) without the inconvenience and added cost of the overwrap.
Another advantage to replacing PVC with a material such as polyethylene is that products such as pure deionized water (U.S.P. for injection) cannot be effectively packaged in PVC because by-products from the PVC packaging material leach into the pure deionized water, contaminating it, whereas materials such as polyethylene can be formulated so as not to contain by-products that leach into the pure deionized water.
Enteral pre-filled packages also benefit in these ways.
Empty parenteral and enteral containers are also widely used, with liquid contents typically being manually added after delivery of the containers by a pharmacist or dietitian. These empty containers, heretofore typically produced in PVC, are often terminally sterilized using autoclaving. Unfortunately, these empty containers also suffer from the problems described above.
Thus advantages exist to using olefin, nylon and composite material containers.
However, heretofore known methods of terminal sterilization, such as autoclaving, are unsuitable for use with polyethylene containers or thin polypropylene containers, because such containers are unable to withstand the temperatures (e.g., between 100 and 200.degree. C.) or pressures of autoclaving. (Polypropylene containers are able to withstand some amount of commercially useful autoclaving, however, are required to be thicker and more expensive to withstand autoclaving than would need be in the absence of this high heat and pressure treatment.) Thus, there exists a need for an approach to deactivating microorganisms in a container that does not require the use of heat that may damage the container or its contents.
Other processes, such as process suggested by Beigler, et al. in the U.S. Pat. No. 4,282,863, entitled METHODS OF PREPARING AND USING INTRAVENOUS NUTRIENT COMPOSITIONS, issued Aug. 11, 1981, employ gamma radiation to achieve terminal sterilization. Unfortunately, the use of gamma radiation creates other problems. For example, gamma radiation is prone to altering the polymeric structure of the olefin container (i.e., gamma radiation degrades the product container integrity), which can result in weakened container integrity, leakage, increased gas permeability and other such problems Also gamma radiation can attack the package and/or its contents to produce other adverse changes, such as darkening, off-colors or color changes, etc. in the package or its contents Furthermore, gamma radiation inherently causes the generation of highly reactive species, such as hydroxyl radicals produced during the gamma radiation of water, that may detrimentally alter the chemical structure of the product being treated. Thus, there exists a need for an improved sterilization process usable with polyolefins and the like that does not employ gamma radiation, or other such reactive processes, to achieve sterilization.
Other problems with heat treatment, i.e., autoclaving, and heretofore employed gamma radiation treatment techniques include the "batch" nature of such processes. Specifically, with heat or gamma radiation treatment, product containers are treated in groups or batches, which problematically requires additional handling of the product not required if an on-line continuous process is used. In addition, careful inventorying and product handling are required in order to assure that each batch is segregated, and separately treated and tested.
In addition, with heretofore employed terminal sterilization techniques it is nearly impossible to monitor all of the parameters necessary to assure adequate deactivation of microorganisms in all of the product packages in a given batch (i.e., parametric control is nearly impossible). (For example, it is difficult to monitor the temperature within the autoclave at enough points that one can assure that every part of every package in the batch received enough heat and saturated steam pressure to achieve adequate deactivation of microorganisms.) Because such parametric control is not generally possible with heretofore employed terminal sterilization techniques, such containers must be observed after, e.g., a fourteen day period following terminal sterilization to determine whether any contaminants are present in selected (or all) containers from each batch. This unfortunately further complicates product and product container treatment and delays usage of the packages and products having been treated. An approach that can be performed in a continuous manner, e.g., as a part of a packaging process, thus eliminating the need for "batch" handling and "batch" testing; and an approach that allows adequate parametric control over processing parameters needed to assure adequate sterility levels, thus eliminating the need for an observation period following treatment, would be highly advantageous.
It is generally accepted that terminally sterilized articles for medical or food applications, when processed, for example, in an autoclave, must attain greater than a 10.sup.-6 survivor probability among microbial contaminants. In other words, there must be less than once chance in a million that viable microorganisms are present in a sterilized article. This level of sterilization is referred to as a sterility assurance level of 10.sup.-6.
Another approach to sterilization of parenteral and enteral containers involves presterilizing the containers using, for example, autoclaving, gamma radiation, chemical treatments or the like, and then filling such containers in an aseptic environment. A sterility assurance level of 10.sup.-6 is needed for most parenteral and enteral applications, and is difficult to verify using heretofore known aseptic filling approaches. (Current aseptic processes are validatable at sterility confidence levels of more than approximately 10.sup.-3 by the use of media fills to demonstrate the absence of growth potential.) Thus, the U.S. Food and Drug Administration, for example, has stated its preference for terminal sterilization processes, even though it recognizes that many products and product packages are damaged by such processes.
Therefore, what is needed is an approach to deactivating microorganisms in a container that achieves an easily verifiable sterility assurance level of at least, for example, 10.sup.-6 but reduces product and product container damage, such as can occur with current terminal sterilization techniques, such as autoclaving or gamma radiation treatment.
The present invention advantageously addresses the above and other needs.